A previous clinical trial in metastatic renal cell carcinoma (RCC) of interferon alpha (IFNA) combined with a cyclooxygenase-2 (COX-2) inhibitor, celecoxib, demonstrated clinical responses only in patients with tumors expressing high levels of COX-2. Thus, a hypothesis was generated that COX-2 inhibition may alter the biology of high COX-2-expressing RCC and enhance the clinical effect of IFNA. This project proposes to prospectively test this hypothesis through a clinical trial of this combination limited to patients with 3+ COX-2 expression and further to explore the mechanisms that drive the anti-tumor effect of IFNA and celecoxib in metastatic RCC. Given that RCC patients with 3+ COX-2 expression represent a significant fraction (20-30%) of the total RCC population, this translational project has clinical relevance. The central hypothesis and long-term goal is to inhibit COX-2 in RCC tumors with high levels of COX-2 expression to overcome immunosuppression and enhance clinical benefit with IFNA. The specific aims are: 1) To estimate the objective response rate of interferon alpha plus celecoxib in metastatic RCC patients with 3+ COX-2 tumor immunostaining. 2) To compare immune parameters in metastatic RCC patients with 3+ COX-2 tumor immunostaining to patients with < 1+ tumor immunostaining and 3) To evaluate the effect of celecoxib and interferon alpha on immune parameters in metastatic RCC patients with 3+ COX-2 tumor immunostaining. An open-label, single-arm phase II trial will be conducted in 34 metastatic RCC patients with 3+ COX-2 tumor immunostaining. Screened metastatic RCC patients with < 1+ COX-2 staining will serve as a control group for evaluation of immune parameters. Patients meeting eligibility criteria will receive IFNA 5 MU s.c. 5x/week and celecoxib 400 mg p.o. BID continuously. Baseline tumor tissue will be stained for COX-2 and infiltrating T cells. Baseline and post- treatment peripheral blood will be analyzed for T regulatory cell number, dendritic cell number and activation status and T cell phenotype (Th1/Th2). This original approach seeks to capitalize on a clinical observation and further explore the cellular immune mechanism of COX-2- mediated immunosuppression. Successful completion of the above aims will lead to a significant therapy advance in metastatic RCC and insight into COX-2 biology. This project seeks to determine how a protein, cyclooxygenase-2 (COX-2), impacts the inherent immune response to kidney cancer and if COX-2 inhibition can enhance the clinical effect of an anti-cancer drug, interferon alpha, in kidney cancer. This project will have broad implications for the immunoregulation of cancer and how expression and modulation of COX-2 expression influences the immune response to cancer. [unreadable] [unreadable] [unreadable]